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The combined cytostatic effect of doxorubicin and gestagens progesterone, medroxyprogesterone acetate, mecigestone, and butagest on doxorubicin-resistant and doxorubicin-sensitive human breast cancer MCF-7 cells was studied by the MTT assay. On the 6th day of incubation progesterone, medroxyprogesterone acetate, mecigestone, and butagest in high concentrations (10(-5) M) potentiated the cytostatic action of doxorubicin in sensitive and resistant cells by 30-50%. Potentiation of the cytostatic effect produced by doxorubicin in sensitive cells is related to intrinsic cytotoxic activity of gestagens. In resistant cells these changes are associated with potentiation of the effect of doxorubicin.

The hormonal compound with the highest cytostatic activity against MCF-7 tumor cells (human breast cancer, BC) and the lowest activity against normal cells (rat skin fibroblasts) was sought among gestagens, androstenes, and antiestrogencytostatics. It was found that antiestrogencytostatics and androstenes had the highest cytostatic activity against tumor cells whereas gestagens and antiestrogencytostatics were least active against fibroblasts. Studies of the activity of the hormonal compounds in combination with doxorubicin on the viability of MCF-7 and rat skin fibroblasts found that all investigated compounds with the exception of dehydroepiandrosterone (DHEA) intensify the cytostatic activity of doxorubicin against tumor cells, the greatest effect seen for antiestrogencytostatics. A chemoprotective effect of androstenes on normal cells was noted.Treatment regimes for cancerous diseases have not yet been standarized despite the efforts of researchers and clinicians. This is apparently due to the fact that each tumor has its own receptor array and individual genetic profile and responds differently to one or another type of therapy. Agonists or antagonists of various steroidal receptors have turned out in several instances to be highly effective in treating hormone -dependent neoplasms. Depending on the age of the patient (reproductive or menopausal), various combinations of antiestrogens, progestins, and even androgens may be used in hormone therapy of human breast cancer (BC) [1]. Herein we report the screening of new synthetic gestagens, antiestrogencytostatics, and androstenes and the comparison of them with existing clinical drugs for tumor model and normal cells. The existing clinical drugs have several side effects and drawbacks (multidrug resistance and glucocorticoid, mineralocorticoid, and androgen side effects of hormone -therapy). Therefore, there is a continuous search for more effective and safer new compounds. Several new steroidal compounds have been synthesized. We studied the following of these: 1) 17a-Acetoxy-3b-butyloxy-6-methylpregna-4,6-dien-20-one (ABMP), a gestagen that does not have a D 4 -3-ketone and has a structure similar to progesterone but, in contrast with it, can be readily absorbed orally [2]. The reference drugs were progesterone (P) and medroxyprogesterone acetate (MPA).2) Po715 and Po716, antiestrogencytostatics that are estrogens having transformed C rings with substituents containing a bis-b-chloroethylamine moiety (Fig. 1) [3,4].We used 11a-derivatives of ethynylestradiol with the bis-b-chloroethylamine moiety bonded to the 3 -position.3) Dehydroepiandrosterone nitrate (DHEAN), androstendiol nitrate (AEDN), and androstendiol dinitrate (AEDDN), which are nitro derivatives of the endogenous androstenes dehydroepiandrosterone and androstendiol, respectively. The reference drugs were androstendiol (AED) and DHEA [5].